Process for preparing zolpidem

ABSTRACT

The invention relates to a process for preparing a compound of formula (I)whereina compound of formula (II), whereinR1 denotes chlorine, bromine, iodine, -O-COCH3, tosylate or mesylate, is reacted with a compound of formula (III), optionally in a suitable diluent and/or in the presence of a suitable added reagent or catalyst,the reaction being carried out in a temperature range from 20 to 80° C.

RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 10/133,830, filed onApr. 26, 2002, now abandoned which claims benefit of U.S. ProvisionalApplication Ser. No. 60/290,747, filed on May 14, 2001 is herebyclaimed.

FIELD OF THE INVENTION

The invention relates to a process for preparing zolpidem.

BACKGROUND OF THE INVENTION

Zolpidem is a known sedative which has the following structure:

EP 0 251 859 describes a process for preparing zolpidem. The six-stepsynthesis starting with a bromoacetophenone is a generally laboriousmethod.

A process for preparing compounds analogous to zolpidem in which2-aminopyridines and corresponding bromoketoamides are reacted isdescribed in the literature (J. of Med. Chem.,1999, Vol. 42,No.19,3934-3941).

The problem of the present invention is therefore to provide animproved, economical process for preparing zolpidem which can be used onan industrial scale.

DETAILED DESCRIPTION OF THE INVENTION

The present invention solves the problem outlined above by the method ofsynthesis described hereinafter.

The invention thus relates to a process for preparing a compound offormula (I)

wherein

a compound of formula (II)

wherein

R¹ denotes chlorine, bromine, iodine, —O—COCH₃, tosylate or mesylate, isreacted with a compound of formula (III),

 optionally in a suitable diluent and/or in the presence of a suitableadded reagent or catalyst,

characterised in that the reaction is carried out in a temperature rangefrom 20 to 80° C.

In a particularly preferred process a diluent is used which is selectedfrom among acetonitrile, N-methylpyrrolidinone, tetrahydrofuran,acetone, ethanol and dichloromethane.

In another preferred process, acetonitrile is used as the diluent.

According to the invention, a process in which the reaction is carriedout at a temperature of about 60 to 75° C., preferably 70° C., isparticularly important.

Also preferred is a process in which the compound of formula (II) isused in a molar ratio of 1:1 to 1:3 to the compound of formula (III).

Particularly preferred is a process in which the compound of formula(II) is used in a molar ratio of about 1:1.3 to the compound of formula(III).

Most particularly preferred is a process in which an added reagentand/or catalyst is used which is selected from among p-toluenesulphonicacid monohydrate, sodium hydrogen carbonate, sodium acetate, pyridine,dimethylaminopyridine, magnesium sulphate, triethylamine,trimethylorthoformate and tetrabutylammonium bromide.

The invention further relates to the compound of formula (II)

wherein

R¹ denotes bromine.

The present invention also relates to a process for preparing a compoundof formula (II), wherein a compound of formula (IV)

is reacted with elemental bromine in a diluent, preferablydichloromethane.

The reaction of a compound of formula (IV) with elemental bromine isgenerally carried out at a temperature of 10 to 50° C., preferably 15 to35° C., more preferably 18 to 30° C., most preferably about 20 or 25° C.

The compound of formula IV is generally used in a molar ratio of 1.5:1to 1:1.5, preferably about 1:1.2, to elemental bromine.

The invention also relates to the use of compounds of formula (II) forpreparing pharmaceutically active compounds.

Preferably, the compound of formula (II) is used to prepare zolpidem.

The invention further relates to a process for preparing a compound offormula (I), this process comprising the following steps:

a) reacting the compound of formula (IV) in an organic diluent at atemperature of 30 to 50° C., preferably about 40° C., with elementalbromine.

b) washing the reaction mixture with water,

c) after phase separation, concentrating the organic phase byevaporation and optionally diluting it with another organic diluent, and

d) reacting the concentrated organic phase of a) to c) with the compoundof formula (III) at 20 to 80° C., preferably 60 to 75° C., preferablyabout 70° C., without isolating the intermediate product.

The present invention further relates to the use of the compound offormula (I) for preparing the pharmaceutically acceptable salts thereof.

The compound of formula (I) is preferably used to prepare zolpidemsemitartrate.

Acids suitable for forming a salt of the compounds according to theinvention include, for example, hydrochloric acid, hydrobromic acid,sulphuric acid, phosphoric acid, nitric acid, oxalic acid, malonic acid,fumaric acid, maleic acid, tartaric acid, citric acid, ascorbic acid andmethanesulphonic acid, particularly tartaric acid.

In a preferred embodiment of the process according to the invention forpreparing the compound of formula II, one equivalent of the compound offormula IV is dissolved in a diluent, preferably glacial acetic acid,ethyl acetate, n-butyl acetate or diethylether, most preferably ethylacetate. A solution of usually 1 to 1.5 equivalents, preferably oneequivalent, of bromine is added dropwise in a diluent, preferably ethylacetate, at a temperature of 40 to 70° C., preferably about 45° C., andstirred for 2 to 24 h, preferably 5 to 15 h, most preferably 12 h, at atemperature of 10 to 50° C., preferably 15 to 35° C., more preferably 18to 30° C., most preferably about 20 or 25° C. The suspension obtained isfiltered, the residue is added to a little water and stirred for about0.5 to 2 h, preferably about 1 h. The suspension is filtered again andthe residue is washed with water. The crystals obtained are dried,preferably in a vacuum drying cupboard at 40 to 80° C., preferably atabout 70° C.

In a preferred embodiment of the process according to the invention forpreparing the compound of formula I, about 1 equivalent of the compoundof formula (II) is placed in a diluent, for example acetonitrile, and asolution of generally 2 equivalents of the compound of general formula(III) and a diluent, for example acetonitrile, is added dropwise at 20to 80° C., more preferably at 40 to 75° C., most preferably at atemperature of about 70° C. within 0.5 to 3 h, preferably 1 to 2 h, morepreferably about 1.5 or 1.75 h. After it has all been added, the mixtureis stirred for 2 to 6 h, preferably 2 to 5 h, more preferably about 2.5to 3 h.

The reaction mixture is then diluted with a diluent, preferablydichloromethane, and washed one to five times, preferably three times,with water. The organic phase is extracted one to five times withhydrochloric acid, preferably 2 N hydrochloric acid. The combined acidphases are adjusted to a pH of between about 7 and 9, preferably to a pHof about 8, using a base, preferably sodium hydroxide solution, morepreferably 20% sodium hydroxide solution. After the reaction mixture hasbeen cooled it is extracted one to five times with an organic diluent,selected from among dichloromethane, toluene, ethyl acetate, n-butylacetate and methyl-tert.-butylether, preferably dichloromethane andethyl acetate, more preferably ethyl acetate. The combined organicphases are dried, preferably with magnesium sulphate, and concentratedby evaporation. The product which crystallises out is mixed with alittle water and stirred for 5 to 20 h, preferably 15 h, and thecrystals are filtered off, washed with water and dried, preferably at 30to 80° C., preferably at 60° C., for 1 to 10 h, preferably 5 h.

In a preferred embodiment of the process according to the invention forpreparing the semitartrate salt of the compound of general formula I,generally 2 equivalents of the compound of formula I are placed in adiluent, preferably methanol, ethyl acetate, Isopropanol or ethanol,more preferably methanol, and a solution of 1 equivalent of (2R,3R)-(+)-tartaric acid in a diluent, preferably methanol, ethanol orisopropanol, more preferably methanol, is added.

A precipitation agent, preferably tert.butylmethylether, anisopropanol/methanol-mixture or a methanol/ether mixture, preferablytert.butylmethylether, is optionally added. The mixture is stirred for 1to 24 h, preferably 12 h, at a temperature of 15 to 30° C., preferablyat about 20 or 25° C. The suspension formed is stirred for a further 0.5to 3 h, preferably about 1 hour at a temperature of 0 to 20° C.,preferably 3 to 10° C., most preferably at about 5° C. The crystalsobtained are filtered, optionally washed with a solvent, preferably withtert.butylmethylether, and the crystals are dried, preferably for 1 to10 h, more preferably for 5 hours at a temperature of 20 to 70° C.,preferably about 50° C.

In a particularly preferred embodiment of the process according to theinvention, about 1 equivalent of the compound of formula (IV) is placedin a diluent, for example ethyl acetate, butyl acetate ordichloromethane, preferably dichloromethane, and heated to 30 to 50° C.,preferably 40° C. Preferably, catalytic amounts, preferably 5 to 6mol-%, of HBr are added to the reaction mixture. Then 1.2 equivalents ofbromine are added dropwise. The reaction mixture is stirred for another60 min, preferably 30 min. The mixture is cooled to about 20 to 25° C.and extracted with water. The organic phase is evaporated down to about10% (v/v) and then diluted with another diluent, preferablytetrahydrofuran, N-methylpyrrolidinone or acetonitrile, preferablyacetonitrile. The mixture is added dropwise to a solution of 1.3equivalents of 6-amino-3-picoline and a diluent, preferablytetrahydrofuran, N-methylpyrrolidinone or acetonitrile, preferablyacetonitrile. The resulting mixture is then stirred for about 2 h at 50to 80° C., preferably 70° C. The reaction mixture is combined with anorganic diluent, preferably toluene, extracted with an aqueous solution,for example 2N hydrochloric acid, and the organic phase is discarded.The aqueous phase is again mixed with an organic diluent, adjusted to apH of about 4, and the organic phase is discarded again. The extractionstep is repeated at a pH of about 8 to 9. After the aqueous phase hasbeen separated off the organic phase is evaporated down to about 10%.The residue is combined with diisopropylether, diethylether ormethyl-tert.butylether, preferably methyl-tert.butylether, and stirredfor about 30 to 60 minutes at about 0 to 15° C., preferably 5° C. Thecrystals formed are washed and dried.

The procedure according to the invention leads to an economical processwith a high space-time yield with regard to the compound of formula I orthe pharmacologically acceptable salts thereof and a high yield andpurity of the intermediate product of formula II, which can be furtherprocessed without being isolated or purified by chromatography.

The Examples that follow serve to illustrate the processes for preparingthe compound of formula I carried out by way of example. They are to beunderstood as examples of possible procedures without restricting theinvention to their contents.

EXAMPLE 1 3-(4-methyl-benzoyl)-2-bromo-propyl-dimethylamide

18.6 g (84.8 mmol) of 3-(4-methyl-benzoyl)-propyl-dimethylamide aredissolved in 50 ml of glacial acetic acid. A solution of 13.55 g (84.8mmol) of bromine and 45 ml of glacial acetic acid is added dropwisewithin 50 minutes at ambient temperature and the mixture is then stirredovernight. The suspension formed is filtered and washed with 30 ml ofglacial acetic acid. The filter residue is added to 200 ml of distilledwater, triturated thoroughly and stirred for 1 hour. The product isfiltered again and washed with another 200 ml of water. The crystalsobtained (21.16 g) are dried for 6 hours in a vacuum drying cupboard at70° C.

Yield 18.18 g of white crystals (71.9% of theory)

Melting point: 119-121° C.

EXAMPLE 2N,N-6-Trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide

50 g (167.7 mmol) of 3-(4-methyl-benzoyl)-2-bromo-propyl-dimethylamideare placed in 500 ml of acetonitrile. A solution of 36.27 g (335.4 mmol)of 6-amino-3-picoline and 350 ml of acetonitrile is added dropwise at60° C. within 1.75 hours and once the solution has all been added themixture is stirred for another 4 hours. The resulting solution isdiluted with 1000 ml of dichloromethane and washed three times with 2000ml of distilled water. Then the organic phase is extracted three timeswith 1000 ml of 2N hydrochloric acid. The combined acid phases areadjusted to pH 8 with 20% sodium hydroxide solution and, after beingcooled, extracted three times with 1 liter of dichloromethane. Theseorganic phases are combined, dried with magnesium sulphate andconcentrated by evaporation. The crystals obtained are triturated with500 ml of distilled water, stirred overnight, filtered off, washed againwith 50 ml of distilled water and the residue is dried in a vacuumdrying cupboard for 5 hours at 60° C.

Yield: 17.94 g of light-brown crystals (45.7% of theoretical).

EXAMPLE 3N,N-6-Trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide

10.0 g (33.5 mmol) of 3-(4-methyl-benzoyl)-2-bromo-propyl-dimethylamideand 7.25 g (67.0 mmol) of 6-amino-3-picoline are dissolved in 170 ml of1,3-dimethyl-2-imidazolidinone and stirred for 3 hours at 60° C. Thereaction mixture is cooled and diluted with 100 ml of dichloromethane.It is then washed five times with 150 ml of distilled water. The organicphase is washed twice with 150 ml of 2N hydrochloric acid. The combinedacid phases are adjusted to pH 8 with 2N sodium hydroxide solution. Themixture is extracted twice with 150 ml of dichloromethane, the organicphases are dried with MgSO₄ and concentrated by evaporation. The brownoil obtained is mixed with 50 ml of n-heptane and stirred for 30minutes. The supernatant diluent is decanted off from the precipitatedproduct which is then washed twice with 10 ml of n-heptane. The residueis evaporated down again, combined with 200 ml of distilled water andstirred for 30 minutes. The product is filtered off, washed with 50 mlof distilled water and dried.

Yield: 2.38 g of beige crystals (23.1% of theoretical.)

Melting point: 194-195° C.

EXAMPLE 4N,N-6-Trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamidesemitartrate

17.94 g (94%) (54.9 mmol) ofN,N-6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide areplaced in 90 ml of methanol. A solution of 4.13 g (27.5 mmol) of (2R,3R)-(+)-tartaric acid and 125 ml of methanol are added, followed by 28ml of methyl-tert.-butyl-ether (MTBE) within 30 seconds. The mixture isstirred for 15 h at ambient temperature. The light-brown suspensionformed is stirred for another 1 hour at 5° C., filtered off, the residueis washed with 50 ml of MTBE, and the crystals are dried for 5 hours ina vacuum drying cupboard at 50° C.

Yield: 18.3 g crystals (87.2% of theoretical.)

EXAMPLE 5N,N-6-Trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide

100 g (0.456 mol) of 3-(4-methyl-benzoyl)-propyl-dimethylamide aredissolved in 400 ml of dichloromethane. 2 g (0.025 mol) of hydrogenbromide are piped into the solution which is then refluxed. Then 86.1 g(0.539 mol) of bromine is added dropwise within 45 minutes and themixture is stirred for 30 min. It is then cooled to ambient temperatureand washed with 600 ml of distilled water. The aqueous phase isdiscarded. The organic phase is evaporated down to about 10% (v/v) andthen diluted with 300 ml of acetonitrile. This solution is addeddropwise within 45 min to a solution of 66.62 g (0.616 mol) of6-amino-3-picoline in 150 ml of acetonitrile at 70° C. and stirred for1.5 h. Then 400 ml of toluene are added at 20-30° C. and the mixture isthen extracted with 500 ml of 2N hydrochloric acid. The toluene phase isdiscarded, the aqueous phase is again combined with 400 ml of tolueneand adjusted to pH 4 with 20% sodium hydroxide solution. The toluenephase is discarded, the aqueous phase is combined with 400 ml of tolueneand adjusted to pH 8.5 with 20% sodium hydroxide solution. The toluenephase is separated off and evaporated down to 10% (v/v). The residue iscombined with MTBE and stirred for 2 h at 5° C. The crystals obtainedare suction filtered, washed with MTBE and dried.

Yield: 43 g of zolpidem (30.7%).

What is claimed is:
 1. A process for preparing a compound of formula (I)

wherein a compound of formula (II)

wherein R¹ denotes chlorine, bromine, iodine, —O—COCH₃, tosylate ormesylate, is reacted with a compound of formula (III),

optionally in a suitable diluent and/or in the presence of a suitableadded reagent or catalyst, wherein the reaction is carried out in atemperature range from 20 to 80° C.
 2. The process according to claim 1,wherein a diluent is used which is selected from the group consisting ofacetonitrile, N-methylpyrrolidinone, tetrahydrofuran, acetone, ethanoland dichloromethane.
 3. The process according to claim 1, whereinacetonitrile is used as diluent.
 4. The process according to claim 1,wherein the reaction is carried out at a temperature of about 60 to 75°C.
 5. The process according to claim 1, wherein the compound of formula(II) is used in a molar ratio of 1:1 to 1:3 to the compound of formula(III).
 6. The process according to claim 1, wherein the compound offormula (II) is used in a molar ratio of about 1:2 to the compound offormula (III).
 7. The process according to claim 1, wherein an addedreagent and/or catalyst is used, selected from the group consisting ofp-toluenesulphonic acid monohydrate, sodium hydrogen carbonate, sodiumacetate, pyridine, dimethylaminopyridine, magnesium sulphate,triethylamine, trimethylorthoformate and tetrabutylammonium bromide.